Streptococcus pneumoniae causes pneumonia and bacteremia in patients infected with the human immunodeficiency virus type 1 (HIV) at a high rate: up to 40-100 times that found in the general population. Despite an adequate initial response to antibiotic therapy in the majority, over 25% of patients will experience a second episode of pneumococcal disease within 6 months. This striking predisposition likely results from ineffective systemic and mucosal immunity against S. pneumoniae. This immunity is dependent upon the presence of pathogen-specific antibodies. Systemic antibodies to the organism, or "natural antibodies", are present in adult sera without overt prior exposure to the organisms. Lack of systemic antibodies in serum is associated with high rates of pneumococcal disease in patients with hypogammaglobulinemia and sickle cell disease. Similarly, baseline levels of anti-pneumococcal IgG have been shown to be depressed in patients with HIV. Analysis of the subclasses of IgG in serum may explain this deficiency. Of the four IgG subclasses, defects in the IgG2 subclass are associated with high rates of pneumococcal infection and with poor responses to the polysaccharide vaccine. Despite elevated levels of total IgG in sera, patients with HIV show decreased levels of IgG2. Therefore, the primary hypothesis of this proposal is that the high incidence of pneumococcal disease among HIV-infected patients is associated with impaired natural systemic immunity to the organism. Antibodies in sera, particularly those specific for the bacterial capsule, are required for opsonophagocytic activity, the functional ability of fresh sera to engulf and kill S. pneumoniae with polymorphonuclear leukocytes (PMNs). Because specific antibody, complement, and PMNs are necessary for opsonization and killing, each of these components of our inherent or natural immune defenses to pneumococcal infection will be examined. In addition to systemic immunity, effective protection against infection requires local mucosal immunity. Infections with S. pneumoniae begin at mucosal surfaces with colonization of the pharynx, followed by aspiration into the lungs. Mucosal immunity, in which antibodies of the IgA class interact with phagocytic cells such as monocyte/macrophages, and with lymphocytes to kill the organism, may also be impaired in persons with HIV. Therefore, this work defines the role of systemic and mucosal antibodies to S. pneumoniae and their effector cells in determining the high incidence of infection and of recurrence in patients with HIV. These data may suggest strategies to prevent and more effectively treat these serious infections, and to identify patients at particularly high risk.